United States Patent
`
`[19]
`
`[11] Patent Number:
`
`4,713,243
`
`Schiraldi et a].
`
`'
`
`[45] Date of Patent:
`
`Dec. 15, 1987
`
`[54] BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND
`PR
`
`[75}
`
`Inventors: Michael T. Schiraldi. East
`Brunswick, N.J.; Martin M. Perl,
`Brooklyn‘ Nix; Howard Rubin.
`Rockaway, NJ.
`
`[73] Assignee:
`
`Johnson & Johnson products, Inc“
`New Brunswick, Nu].
`
`[21] APP]. N05 87419.)“
`
`-
`
`[22] Filed:
`
`Jun. 16, 1986
`
`Int. Cl.‘ .................... .. AGIN 59/ 10; AfilK 33/16
`{51]
`[52] U.S. Ci. .................................. .. 424/151; 424/449;
`424/435
`[58] Field of Search ................. .. 424/21, 28, 449, 435,
`424/ 151
`
`
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`......................... 424K115
`4,292,299
`9/1931 Suzuki et a].
`
`4,421,738 12/ 1983 Yamigawa et a].
`..
`424/21
`4,517,173
`5/1985 Kizawa et a].
`...................... .. 424/16
`.
`.
`Puma)? Examiner—Peter F. Kulkcsky
`[57]
`ABSTRACT
`A bioadhesive extruded single or multi-layered thin
`film, especially useful in intra~oral controlled-releasing
`delivery, having a water soluble or swellable polymer
`matrix bioadhesive layer which can adhere to a wet
`mucous surface and which bioadhesive layer consists
`essentially of 40—95% by weight of a hydroxypropyl
`cellulose, 5—6096 of a homopolymer of ethylene oxide,
`{ii—10% of a water-insoluble polymer such as ethyl cellu-
`lose, propyl cellulose, polyethylene and polypropylene,
`and 2—10% of a plasticizer, said film having incorpo-
`rated therein a medicament, e. g., anesthetics, analgesics,
`anticaries agents, anti-inflammatories, antihistamines,
`antibiotics. antibacterials. fungistats, etc.
`
`9 Claims, No Drawings
`
`Dr. Reddy's - EX1014
`
`Page 1
`
`Dr. Reddy's - EX1014
`Page 1
`
`

`

`
`
`1
`
`4,713,243
`
`'
`
`BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND PROCESS
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention relates to a controlled-releas-
`ing medicament-containing preparation for intra-oral
`use, and is more especially concerned with such a prep-
`aration (and the process of using it) in the form of a very
`thin extruded thermoplastic film (which can be in single
`layer or laminated multi-layer form) having at least one
`bioadhesive layer containing 40-95% of a thennOplastic
`cellulose ether and 540% of a homopolymer of ethyl-
`ene Oxide which can adhere to the mucosa of the oral
`cavity. The extruded film drug delivery system of the
`present invention, which has incorporated therein the
`medicament to be dispensed, is so thin and flexible when
`Wet as to be unobtrusive to the patient after it has been
`properly positioned and placed in the mouth.
`2. Description of the Prior Art
`Several systems have previously been described
`which pertain to the delivery of drugs into the oral
`cavity. These include:
`1. Treatment of periodontal disease with tetracycline,
`chlorhexidine or metronidazole loaded into hollow
`cellulose acetate fibers. These fibers are packed in the
`periodontal pockets and provide controlled release of
`the drug to the infected area.
`2. Cast films containing ethyl cellulose/propylene gly-
`col With cltlorhexidine or metronidazole for treat-
`ment of periodontal disease.
`3. An orthodontic appliance with a hydroxyethyl me-
`thacrylate/methyl methacrylate copolymer
`(HE-
`MA/MMA) matrix. Sodium fluoride is incorporated
`into the HEMA/MMA matrix to provide sustained
`fluoride release and enhanced anticaries activity.
`HEMA/MMA with fluoride may also be attached to
`the tooth in the form of a wafer-like tablet.
`
`films
`4. Silicone/ethyl cellulose/polyethylene glycol
`containing sodium fluoride are applied as coatings on
`orthodontic bands or in chewing gum. Controlled
`release of fluoride and anticaries activity is claimed.
`The ab0ve systems are discussed in the “The Compen-
`dium of Continuing Education" Vol VI, No. 1, January
`1985 p. 27—36 review article “Controlled Drug Deliv-
`ery: A New Means of Treatment of Dental Disease”, by
`.l. Max Goodson, D.D.S., PhD. of the Forsyth Dental
`Center. Other systems, described in GB patent applica-
`tion
`No.
`2,042,888
`and
`U.S.
`Pat.
`Nos.
`4,292,299/4,226,848 (Teijin Ltd., Japan), use combina-
`tions of cellulosic and polyacrylate polymers. The pre-
`ferred materials are hydroxypropyl cellulose (“Klucel”)
`and a copolymer of acrylic acid ("Carbopol") that is
`administered in the form of thin tablets (discs), granules
`or powder. Other polymers that might be added are
`vinyl copolymers, polysaccharides, gelatin and colla-
`gen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
`Japan} uses various 'celIuloses in a multiwlayered non-
`extruded cast film preparatiou.
`Examples of prior art products currently on the mar-
`ket include ointments such as ORABASE“ with Benzo-
`caine (Squibb), Kenalog“ (Triamcinolone Acetonide) in
`ORABASE“ (Squibb) and Mycostatin“ (Nystatin) oint-
`ment (Squibb).
`
`2
`The prior art products and delivery systems de~
`scribed above are useful but have the following disad-
`vantages:
`Tablets, appliances, hollorav fibers are “bulky” in the
`mouth. are difficult to keep in place and inconve-
`nient to apply.
`Ethyl cellulose and/or silicone films do not adhere to
`mucosal tissue.
`Ointments (i.e., ORABASE‘} have an unpleasant feel
`and do not last very long.
`Except for ORABASE“, all the foregoing systems
`require professional application to the tooth or
`periodontal pockets.
`The bioadhesive film of the present invention alleviates
`many of the above problems. It may be applied easily by
`the consumer. It has very little or no mouthfeel. it has
`good adhesion to the mucosal
`tissues, and provides
`controlled release of the medicament.
`
`OBJECT OF THE INVENTION
`
`It is an object of this invention to provide an extruded
`film that is an effective and convenient intra—oral drug
`delivery system and method for applying and delivering
`controlled dosages of therapeutic agents into the oral
`cavity. This technology may also be extended for con-
`trolled drug delivery in skin care, gynecological appli-
`cations, wound care and like uses.
`
`SUMMARY OF THE INVENTION
`
`The invention involves a pharmaceutically accept-
`able controlled-releasing medicament-containing ex-
`truded single or main-layered thin film. capable of ad-
`hering to a wet mucous surface, comprising a water
`soluble or swellable polymer matrix bioadhesive layer
`which can adhere to a wet mucous surface and which
`bioadhesive layer consists essentially of 40—95% by
`weight of hydroxypropyl cellulose 5—60% of a homo-
`polymer of ethylene oxide. 0-10% of a water-insoluble
`polymer selected from the group consisting of ethyl
`cellulose, propyl cellulose, polyethylene and polypro-
`pylene, and 240% of a plasticizer, said film having
`incorporated therein a phatmaceutically effective
`amount of said medicament.
`The present invention is directed to an extruded sin-
`gle or multi-layered laminated thin (1—10 mils or
`0.025—0.25 mm) film, composed of selected water solu-
`ble and/or insoluble polymers. Various therapeutic
`agents are incorporated into the film during manufac-
`ture which are useful for treatment of oral disorders
`(i.e., denture discomfort, caries, periodontal disease,
`aphthous ulcers, etc.).
`The extruded film of the present invention must have
`at least one bioadhesive layer, but may also have a reser-
`voir layer and/or an outer protective barrier membrane
`layer. The therapeutic agent may be incorporated into
`any or all of the layers. when properly formulated and
`fabricated, these films will adhere to wet mucosal sur-
`faces, provide a protective barrier for injured flame and
`deliver controlled/sustained dosages of medication to
`the infected areas. The film may be designed for local-
`ized drug delivery (i.e., the periodontal pocket, an aph-
`thous lesion), or may allow diffusion ofthe drug into the
`oral cavity.
`-
`An example of a non-localized system would be the
`delivery of sodium fluoride for caries prevention. A
`single or laminated film with good adhesion to the tooth
`or mucosal tissue may be employed in which the fluo-
`ride release rates may be controlled by varying film
`
`
`
`Page 2
`
`Page 2
`
`

`

`3
`solubilities and/or concentration of fluoride in a multi-
`layered film.
`An example of a localized application of medication
`would be in the treatment of aphthous lesions. A lami—
`hated two layer film with benzocaine incorporated into
`the adhesive layer would directly contact the injured
`mucosa. The outer layer would consist of non-soluble/-
`non-adhesive polymers that provide durability, protec-
`tion and directs the delivery of benzocaine toward the
`lesion.
`The film forming polymers that are useful in this
`invention are selected from pharmaceutical grade mate-
`rials, or those that are considered generally regarded as
`safe (GRAS) as food additives. They include, hydroxy-
`propyl cellulose, and polyethylene oxide homopoly-
`mers. Small amounts of other polymers, e.g., polyvinyl
`ether-maleic acid copolymers and the like may be used
`in small amounts as well, replacing a small portion of
`the other polymers. The above materials are either
`water soluble of swellable and are most useful in the
`bioadhesive layer of the film. Various non-soluble poly-
`mers may also be incorporated for modification of the
`film’s permeability properties, such as ethyl cellulose,
`propyl cellulose, polyethylene, polypropylene and car-
`boxymethylcellulose (free acid). By varying the ratios
`of the above polymers both the solubility and the adhe-
`sive properties of each layer of film may be controlled.
`Therefore, depending on the desired delivery rate, the
`type of disorder to be treated, the area to be treated and
`the medication being administered it is possible to cus—
`tom design the film by selecting and blending various
`polymers. The final film product may also be fabricated
`into flexible tapes of varied thickness and width, “spots”
`of different sizes and shapes or other pre-shaped forms.
`'The medicaments and pharmaceutical agents set forth
`in the prior art discussed above may generally be deliv-
`ered by the drug delivery system of the present inven-
`tion. Usable medicaments are those which are capable
`of withstanding the heats and pressures generated in the
`extrusion process involved in making the film of the
`present invention. Preferred medicaments include:
`Anesthetics/Analgesicsabenzocaine, dyclonine HCl,
`phenol, aspirin, phenacetin, acetaminophen, potas—
`sium nitrate, etc.
`sodium mono‘
`Anticaries Agents-sodium fluoride,
`fluorophosphate, stannous fluoride, etc.
`Anti-inflammatories-hydrocortisone acetate, triamcino-
`lone acetonide, dipotassium, glycyrrhizinate, etc.
`Antiliistaminesvchlorpheniramine maleate, ephedrine
`HCL, diphenhydrnmine HCL, etc.
`Antibiotics-Le, tetracycline, doxycycline hyclate, me-
`clocycline, minocycline, etc.
`Antibacterials-chlorhexidine, cetyl pyridinium chlo-
`ride, benzethonium chloride, dequalinium chloride,
`silver sulfadiazene, phenol, thymol, hexedine, hexeti-
`dine, alexidine, etc.
`Fungistats-nystatin, miconazole, ketoconazole, etc.
`The above are illustrative examples of therapeutic
`agents that are used to treat oral disorders. The present
`invention is not to be limited to these specific materials
`especially where it is intended to deliver drug outside of
`the oral cavity e.g. to skin where other drugs may be
`desirable.
`
`The film of the present invention has the advantage of
`being an extruded film, rather than a cast film. When a
`multi-Iayered film is involved, the different layers can
`be coextruded and then laminated together, or else each
`layer can be separately extruded one on the other, and
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`.
`
`
`
`4,713,243
`
`4
`then laminated together, so that the final multi-layered
`film is still very thin. The films of the present invention
`can be made in thicknesses of only 1—10 mils or
`0025—025 mm. The films are so thin that when placed
`in the mouth after they become wet they soon become
`unobtrusive, and hardly noticeable by most patients.
`The film must always have a bioadhesive layer,
`which enables it to adhere to wet mucosal surfaces. The
`bioadhesive layer has 40—95% of hydroxypropyl cellu-
`lose, 5-60% of a homopolymer of ethylene oxide and
`240% of a glycol plasticizer (all percents are % by
`weight).
`The Hydroxypropyl cellulose (HPC), useful for pur-
`poses of the present invention is commercially available
`from Hercules, Inc. (Wilmington, DE) under the trade-
`name KLUCEL‘. Preferred grades include Klucel MF,
`with a molecular weight around 600,000 and having a
`viscosity of 4,000-6,000 cps (Brookfield) in 2 percent
`water solutions, or Klucel HF, having a molecular
`weight around 1,000,000 and viscosity of 1500-2500 cps
`in 1 percent water solution. In general, any HPC having
`a Molecular Weight above about 100,000 is useful for
`purposes of this invention.
`The homopolyrner of ethylene oxide useful for pur-
`poses of the present invention has a relatively high
`molecular weight,
`i.e., above 100,000 and preferably
`above 3,000,000. Such polymers are commercially
`available from various sources. The Union Carbide
`Corporation material, “Polpo WSR—301", which has a
`molecular weight of approximately 4,000,000-5,000,000
`is most preferred for purposes of the present invention.
`The “plasticizer” useful for purposes of the present
`invention are selected from glycols such as propylene
`glycol and polyethylene glycol; polyhydric alcohols
`such as glycerin and sorbitol; glycerol esters such as
`glycerol
`triacetate;
`fatty acid triglycerides such as
`NEOBEE“ M-5 and MYVEROLS‘; mineral oil; vege-
`table oils such as castor oil, etc.
`For the uses for the present invention contemplated
`here, the plasticizer should be non—toxic. The purpose of
`the plasticizer is to improve polymer melt processing by
`reducing the polymer melt viscosity and to impart flexi-
`bility to the final product.
`The preferred .plasticizer for use in the present inven-
`tion is either propylene glycol or polyethylene glycol
`(such as is available from Union Carbide Corporation as
`their series of Carbowaxes which runs from 200 to 600
`molecular weight, of which we prefer to use Carbowax
`400, which has a molecular weight of 400, average.
`In addition to the polymers and plasticizer which are
`required ingredients of the films of the present inven-
`tion, minor amounts of other non-essential but custom-'
`aty ingredients will often be used if desired, e.g., antiox-
`idants, preservatives, flavors, colorants.
`DETAILED DESCRIPTION
`
`The following examples will serve to illustrate the
`present invention in greater detail. The units shown in
`the examples are parts by weight. The thickness of the
`layers is expressed in either mils (0.001 inches) or milli-
`meters. For easy cOnversion, 4 mils is approximately
`equal to 0.1 mm.
`
`EXAMPLE 1
`
`_ Triple Layered Laminate Containing Sodium Fluo-
`ride for Anticaries Protection
`This three layered film laminate is comprised of a
`“bioadhesive” layer, a sodium fluoride “reservoir”
`
`Page 3
`
`
`
`Page 3
`
`

`

`4,713,243
`
`
`
` 6
`
`continued
`
`185
`Die Zone I
`185
`Die Zone 2
`
`Die Zone 3 135
`
`Each layer is extruded separately with the first layer
`extruded as a “free film". SucceSSive layers are extruded
`Onto each other and laminated by passing them through
`heated stainless steel rollers.
`Test Results:
`In vitro fluoride ion release studies were conducted
`
`an samples of the above described triple laminate film
`measuring 0.5 crnX 1.25 cm (0.625 cml) according to
`the following procedures:
`The test sample is adhered to a glass slide by prewet-
`ting the film and placing the bioadhesive layer on the
`glass surface. The slide is then immersed in a beaker
`containing l00 ml of distilled water with continuous
`stirring. Five milliliter aliquots are withdrawn from the
`solution, at prescribed time intervals, and analyzed for‘
`fluoride content with an Orion Ionanlyzer equipped
`with a fluoride specific electrode. Release rates are then
`calculated from the data.
`The results obtained indicated fluoride release rates in
`the order of 005-02 mgs/cmZ/hr for 24 hours. This
`falls within the desired range for maintaining constant
`low levels of fluoride in the mouth and enhanced anti-
`caries activity. Release rates may be tailored to desired
`use levels by modification of the film composition and
`construction.
`
`EXAMPLE 2
`
`Single Layer Adhesive Film Containing Hydrocorti-
`sone Acetate (0.5%) As An Anti-Inflammatory Agent
`The composition of the film, which was 0.1 mm.
`thick, was as follows:
`
`Ingredients
`9:: w/w
`Ethylene Oxide Homopolymer
`59.4
`(Polyox‘ WSR—JOI)
`Hydroxypropyl Cellulose
`(Klucel‘ MF)
`Polyethylene (AC-6A)
`Propylene Glycol
`Polyethylene Glycol 400
`Butylaled Hydroxy Toluene (BHT)
`FCC (preservative)
`0.5
`Hydrocortisone Acetate
`[00.0
`
`5.0
`3.0
`2.0
`0.1
`
`30.0
`
`The powder blending process and extruder conditions
`used were the same as those described in Example I for
`the "bioadhesive layer" of the sodium fluoride trilami-
`nate. In vitro tests were performed on the above film
`and demonstrated a prolonged drug release pattern.
`EXAMPLE 3
`
`Single Layer Adhesive Film Containing Triamcino-
`lone Acetonide (0.1%) As An Anti-Inflammatory
`The composition of the film. which was 0.1 mm.
`thick, was as follows:
`
` Ingredients % wr'w
`
`Ethylene Oxide Homopolymer
`59.9
`(Polyox WSR-JUI)
`Hydroitypropyl Cellulose
`(Klucel MF)
`
`29.9
`
`ID
`
`is
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The prooesa used to make the above laminate was:
`3. Powder Blending-Each layer is made soparately and
`all ingredients used therein except propylene glycol
`and Neobee M-S (liquid plasticizers) are placed in 21
`Patterson Kelley (PK) V-blender equipped with liq-
`uid addition capabilities. The ingredients which are
`all powders are blended for approximately 10-15
`minutes while the liquid plasticizer is slowly added to
`the mix. Three separate powder blends are made, one
`for each layer.
`b. Extrusion Process-A standard Johnson 2-; inch vi-
`nyl/polyolefin extruder equipped with a single three
`stage screw was used to extrude the “powder blend”.
`The temperature conditions for the water soluble
`powders are however quite different from those used
`for vinyls and polyolefins. The temperature CC.)
`profile for the "reservoir" and “membrane layers” of
`the triple laminate was as follows:
`
`Barrel Zone I
`[00
`Barrel Zone 2
`us
`Barrel Zone 3
`135
`Barrel Zone ‘3
`145
`Barrel Zone 5
`160
`Barrel Zone 6
`ill]
`Adapter
`130
`Die Zone 1
`180
`Die Zone 2
`180
`
`Die Zone 3 I30
`
`The films which had a width of 18 inches, were ex-
`truded at approximately 20 feet/minute through a flat
`lipped die. The temperature profile for the “bioadhesive
`layer" was:
`
`Barrel Zone 1
`I25
`Barrel Zone 2
`I40
`Barrel Zone 3
`165
`Barrel Zone 4
`I‘ll)
`Barrel Zone 5
`135
`Barrel Zone 6
`135
`Adapter
`[35
`
`5
`layer and, an “outer protective barrier membrane”
`layer, in which the composition and thickness of each
`layer are as shown below:
`
`Outer
`Protective
`Barrier
`% w/w
`Bio-
`Reservoir Membrane
`adhesive
`Layer
`Layer
`Layer
`(4 mils)
`{l mil)
`(1 mil)
`
`Ingredients
`(0.l mm}
`(0.025 mm)
`(0.025 mm)
`Polyethylene oxide
`60.0
`—
`—
`homopolymer (Union
`Carbide-Polyox' WSR—ifll)
`Hydroxypropyl Cellulose
`(Hercules. inc-Klucel‘ MFJ
`Polyethylene (Allied
`Chemical-6A)
`(Low Density)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol
`400 (Union Carbide)
`Ethyl Cellulose (Hercules,
`Inc-hilij
`Caprylichapric
`Triglyceride (PVO
`Incorporated-Neobee Md)
`
`list)
`—
`Sodium Fluoride. U.S.P.
`0.4
`
`
`100.0100.0 100.0
`
`30.0
`
`5.0
`
`3.0
`2.0
`
`-
`
`—
`
`20.0
`
`24.0
`
`—
`
`—
`—
`
`59.0
`
`5.0
`
`—
`
`—
`—
`
`69.6
`
`6.0
`
`
`
`Page 4
`
`

`

`4,713,243
`
`-continued
`____—_-—————-
`_._._.—__._————-——
`Ingredients
`9‘5 wr’w
`Polyethylene (AC-6A)
`5.0
`Propylene Glycol
`3.0
`Polyethylene Glycol 400
`2.0
`BHT
`0.1
`
`0.1
`Triarncinolone Aoetonide
`100.0
`
`5
`
`The powder blending process and extruder conditions 10
`used to make the film of this Example 3 were the same
`as those of the “bioedhesive layer” of Example 1.
`Other desired active medicament ingredients may be
`incorporated into the adhesive films of any of Examples 15
`1-3 in place of the particular medicament used in said
`examples. These include Benzooaine (analgesic), Potas-
`sium nitrate (analgesic), Silver sulfadiazene (antimicro-
`bial),
`Chlorhexidine (antimicrobial), miconazole nitrate 20
`(antifungal), Benzethonium chloride (antimicrobial),
`Tetracycline (antibiotic) and other similar therapeutic
`compounds.
`
`EXAMPLE 4
`Analgesic Films with Potassium Nitrate
`This example shows 5 variations of the film having
`different solubilities, resulting in different release rates.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`
`-continued
`100.00
`
`B.
`
`Outer protective/barrier layer
`Hydrorypropyi Cellulose
`(Klucel‘I MF)
`Ethyl Cellulose
`20.00
`
`Polyethylene Glycol 400
`2.00
`100.00
`
`78.00
`
`Part A was extruded on a Johnson extruder followed by
`subsequent extrusion and lamination of Part B to A.
`Samples were applied to oral lesions, and provided
`profound anesthetic effects
`(lasting several hours)
`within minutes of application.
`The identical two-layer laminate may also be made
`by coextruding the inner medicated bioadhesive layer
`(Part A) and the outer protective barrier layer (Part B)
`through separate die slots within a coextruder and lami-
`nating the two layers together.
`EXAMPLE 6
`
`Anesthetic Films with Phenol and Dyclonine HCl
`Four variations of a single layer bioadhesive film
`were made as shown below:
`
` Ingredients i 2 3 4
`
`
`
`
`Polyethylene oxide homo-
`59.10
`54.00
`59.?0
`58.20
`polymer (Polycr‘ WSRJGI)
`Hydroxypropyl Cellulose
`(KluceI HF)
`4.85
`4.98
`4.50
`4.93
`Ethyl Cellulose
`2.91
`2.99
`2.70
`1.96
`Propylene Glycol, U.S.P.
`1.94
`1.99
`1.80
`1.9?
`Polyethylene Glycol 4-00
`0.l0
`0.09
`0.09
`0.09
`BHT. F.C.C.
`—
`-—
`—
`1.50
`Phenol, U.S.P.
`
`Dyclonine HCI 3.00 - 10.00 0.50
`
`
`
`
`29.45
`
`26.9]
`
`29.75
`
`29.00
`
`Following the procedures for the bioadhesive layer of
`Example I, the powders were blended in P-K blender
`equipped with liquid addition capabilities. Resulting
`powders were extruded on a Killian laboratory-sized
`extruder.
`
`EXAMPLE 7
`
`Silver Sulfadiazene Films-Antimicrobial
`Three different single-layered bioadhesive films con-
`taining 1.0% 0.5% and 0.5% respectively of silver sul-
`fadiazene (SSD) were prepared on a heated Carver
`laboratory press (designed to simulate extruded condi-
`tions) as shown below.
`
`% W/w
`
`A
`60.00
`
`23.9
`
`Ingredients
`Polyethylene oxide homopolymer
`(Polyox‘ WEE-301)
`Hydroxypropyl Cellulose
`(Klucel‘ HF)
`Polyethylene (AC-6A)
`5.0
`5.0
`Propylene Glycol, U.S.P.
`3.0
`3.0
`Polyethylene Glycol 400
`2.0
`2.0
`BHT. F.C.C.
`0.1
`0.1
`
`Silver Suiladiazine
`1.0
`0.5
`
`HIM:| 153.0
`
`B
`60.00
`
`29.4
`
`Effects on wound repair and activity against Staphylo-
`coccus auraus were evaluated in the guinea pig model.
`Full-thickness excisions were inoculated with 3.8X105
`organism, (Staph. duress) and wound surface microbi-
`
`- Page 5
`
`
`
`
`
`1
`23.75
`
`2
`5100
`
`96 w/w
`3
`55.00
`
`4
`55.00
`
`S
`57.00
`
`‘
`
`.
`"Ingredients
`Polyethylene oxide
`homopolymer (Polyox‘
`WSR—Jfll}
`Hydroxypropyl Cell-
`--ulose, N.F. (Klucel‘ HID
`Hydroxypropyl Cell-
`ulose. N.F. (Klucei' MF)
`"Ethyl Cellulose
`‘lPoiyethylene GlycoHOO
`.mPolyerhylene Glycol 8000
`Propylene Glycol. U.S.P.
`BHT, F.C.C.
`Potassium Nitrate. F.C.C.
`
`68.30 —
`
`—
`
`—
`
`——
`
`—
`
`28.40
`
`29.90
`
`22.40
`
`22.40
`
`4.75
`1.90
`1.90
`0.95 —
`—
`2.85
`0.l0
`0.!0
`5.00
`5.00
`
`5.00
`2.00
`—
`3J1!)
`0.10
`5.00
`
`12.50
`2.00
`_
`3.00
`0.10
`5.00
`
`12.50
`2.00
`_
`3.00
`0.03
`3.00
`
`The above ingredients are blended in a Patterson-Kelly
`powder blender equipped with liquid addition capabili-
`ties. The resulting powder blend is then extruded into
`film on a Killion or Johnson vinyl extruder using pro-
`cessing procedures similar to those of the bioadhesive 50
`layer of Emnple 1.
`
`EXAMPLE 5
`
`Anesthetic Films with Benzocaine (Laminate)
`This is an example of a two-layer laminate. The pro- 55
`cessng conditions used were similar to those of the
`bioadhesive layer and outer protective barrier mem~
`brane layer of Example I.
`
`
`A-
`
`Polyonyethylene Homopolyrner
`(Polyott‘ “(SR-301)
`Hydroxypropyi Cellulose. NF.
`(Klucei' MF)
`Polyethylene (AC-6A)
`Propylene Glycol. {LS-P.
`Polyethylene Glycol 400
`BHT. F.C.C.
`Benzocaine, U.S.P.
`
`5"
`
`65
`
`57.00
`
`28.40
`
`4.75
`2.35
`1.90
`0.10
`5.00
`
`
`
`Page 5
`
`

`

`
`
`4,713,243
`
`9
`ology samples taken 10 minutes and 24 hours after treat-
`ment. Test films were placed on the wound and covered
`with BIOCLUSIVE“ Transparent Dressings secured
`with elastic tape. Wound contraction was measured
`Over an eight-day period using 0FTOMAX‘ Comput—
`er—Assisted Image Analysis. The three films tested were
`the following:
`A. 1.0% Silver Sulfadiazene, 125“ 0/2 minutes/4 tons
`B. 0.5% Silver Sulfadiazene, 125° C./2 minutes/4 tons
`C. 0.5% Silver Sulfadiazene, 150° C./3 minutes/4 tons
`SILVADENE Cream and an untreated occluded
`control. The results indicated that:
`l. SILVADENE‘ treated wounds significantly inhib-
`ited full-thickness wound contraction.
`2. Film A, B and C inhibited wound contraction relative
`to that of BIOCLUSIVE‘ dressed wounds.
`
`3. The three SSD films each permitted substantially
`faster wound contraction than that of wounds treated
`daily with SILVADENB‘ cream.
`4. All films were very active against S. aureus 24 hours
`after inoculation.
`
`The films may be scaled up by using an extruder. This
`example demonstrates the feasibility of such a film to
`perform its intended purpose. Use of a press for larger
`samples would result in a non-uniform and lower-qual-
`ity film than an extruded film.
`Based on the above findings, the films were very
`effective antibacterial agents, while mildly inhibiting
`wound contraction. They offer clinicians a convenient
`and more effective delivery system for antimicrobials
`which can be place in wounds beneath any dressing or
`can be laminated to any acceptable dressing face.
`What is claimed is:
`
`l. A pharmaceutically acceptable controlled-releas-
`ing medicament-containing extruded single or multi-
`layered thin film, capable of adhering to a wet mucous
`surface, comprising a water soluble or swellable poly-
`mer matrix bioadhesive layer which can adhere to a wet
`mucous surface and which bioadhesive layer consists
`essentially of 40—95% by weight of a hydroxypmpyl
`cellulose having a molecular weight above 100,000,
`5—60% of a homepolymer of ethylene oxide having a
`molecular weight from 3,000,000 to 5,000,000, 040%
`of a water-insoluble polymer selected from the group
`consisting of ethyl cellulose, propyl cellulose, polyeth-
`ylene and polypropylene, and 2-10% of a plasticizer,
`said film having incorporated therein a pharmaceuti-
`cally effective amount of said medicament.
`2. The extruded film of claim 1, made in a form which
`is so thin and flexible when wet as to be unobtrusive to
`the patient when properly positioned and placed in the
`patients mouth.
`
`[0
`
`I5
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`10
`3. The extruded film of claim 2 having a thickness no
`greater than 0.25 millimeters.
`4. The extruded film of claim 1, in single layer form,
`which also contains up to 10% by weight of a non-solu-
`ble polymer selected from the group consisting of ethyl
`cellulose, polyethylene, polypropylene and carboxy-
`methyl cellulose free acid.
`5. The extruded film of claim 1, in multi-layer lami-
`nated form, which is addition to the bioadhesive layer
`also contains a reservoir layer in which at least a major
`portion of the medicament is contained.
`6. The extruded multi-layer film of claim 5 in which
`the reservoir layer consists essentially of a polymer
`matrix comprised of both a water soluble or swellable
`polymer and a non-water soluble polymer selected from
`the group consisting of ethyl cellulose, propyi cellulose,
`polyethylene and polypropylene, and also hydroxypro-
`pyl cellulose.
`'l. The extruded film of claim 1 in multi-layer lami-
`nated form, which in addition to the bioadhesive layer
`also contains an outer protective-barrier membrane
`layer.
`8. The extruded multi-layer film of claim 7 in which
`the outer protective-barrier membrane layer is thinner
`than the bioadhesive layer, and said outer protective
`barrier layer consists essentially of a polymer matrix of
`a major proportion of a non-water-soluble polymer
`selected from the group consisting of ethyl cellulose,
`propyi cellulose, polyethylene and polypropylene, and
`a minor proportion of hydroxypropyl cellulose.
`9. The extruded multi-layer film of claim 1 in the
`form of a triple layered laminate containing sodium
`fluoride for anticaries protection having the following
`composition:
`
`Outer
`Protective
`Barrier
`95 wfiw
`Bio-
`Reservoir Membrane
`adhesive
`Layer
`Layer
`Layer
`
`Ingredients
`(0.1 mm)
`(0.025 mm)
`(0.025 mm)
`Polyethylene oxide
`60.0
`—
`—
`homopolyrner
`(MW 3,000,000 minimum)
`Hydroxypropyl Cellulose
`(MW £000,000}
`Polyethylene (Low Density)
`Propylene Glycol, USP.
`Polyethylene Glycol
`(MW 400)
`Ethyl Cellulose
`69.6
`59.0
`CaprylicKCapric
`5.0
`6.0
`Triglyceride
`
`—
`Sodium Fluoride
`[6.0
`0.4
`
`
`100.0100.0 [03.0
`
`20.0
`
`—
`—
`—
`
`24.0
`
`-_
`—
`—
`
`30.0
`
`5.0
`3.0
`2.0
`
`—
`—
`
`
`
`Page 6
`
`Page 6
`
`